Fenofibrate-containing composition

ABSTRACT

A novel fenofibrate-containing composition having equivalent bioavailability, when compared to conventional capsules, is effective in reducing the size of the conventional capsule preparations. The fenofibrate-containing composition comprises the following formula:  
                                               (a) fenofibrate   100   parts by weight,         (b) a solid surfactant   3 to 4   parts by weight,         (c) lactose   1 to 2   parts by weight, and         (d) magnesium stearate   1 to 2   parts by weight,                                 
 
     in admixture with a binder and a disintegrator, wherein the sum of said binder and said disintegrator is 17 to 20 parts by weight, and the fenofibrate and the solid surfactant are co-micronizates.

TECHNICAL FIELD

[0001] The present invention relates to a pharmaceutical compositionwhich is effective in reducing the size of fenofibrate-containingpreparations (i.e., in minimizing fenofibrate-containing dosage forms).

BACKGROUND ART

[0002] Fenofibrate, a compound with the chemical name of isopropyl2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropionate, lowers the levels ofserum cholesterol, LDL-cholesterol, and triglyceride, and raisesHDL-cholesterol levels. Fenofibrate has been appreciated, worldwideincluding in Japan, as an antihyperlipidemic agent which improvesoverall lipid metabolism.

[0003] Fenofibrate has been conventionally formulated as a hard capsuleform (hereinafter, may be briefly referred to as “capsule”). Fenofibratecompositions with improved bioavailability have been studied. Forexample, Japanese Examined Patent Publication No. Hei 7-14876 (JP7-14876, B (1995)) has disclosed the composition containing ahomogeneous mixture of co-micronized particles (hereinafter, may bereferred to as “co-micronizate”) of fenofibrate and a solid surfactant.

[0004] Generally, when a drug must be orally taken over a long period oftime, first, the fewer number of capsule per dose as well aspreparations of easily ingestable size greatly leads to improvement ofpatient's compliance with drug-taking. Such improvement of thedrug-taking compliance becomes more important especially in the case ofthe elderly who experience hypofunction in swallowing.

[0005] For hyperlipemia, an indication to which the fenofibratepreparations are applied, in most cases, patients are required to takethe drug over a long period of time such as a yearly basis, also amajority of the patients are elderly persons, and further there are lotsof cases where several types of concomitant drugs are frequentlyprescribed due to complications with diabetes and arteriosclerosis.Under such circumstances, it has been strongly desired to developminimized and easily ingestable preparations without increasing thenumber of capsule per dose.

[0006] In the case of the above prior art composition containing theco-micronizate of fenofibrate and the solid surfactant (hereinafter,referred to as “co-micronized composition”), it enables the improvementin bioavailability, leading to the reduction of 300 mg fenofibratedosage per day to ⅔, 200 mg. However, even in the case of suchco-micronized compositions, when formulated, pharmaceutical additivessuch as an excipient, a binder and a disintegrator (hereinafter, alsosimply referred to as additives) are required to be added. In the aboveprior art, the total amount of fenofibrate and the additives per capsulefor the capsule preparation containing 200 mg of co-micronizate offenofibrate becomes approximately 297 to 350 mg (the preparationexamples I and II in Japanese Examined Patent Publication No. Hei7-14876 (JP 7-14876, B (1995))). To fill up them in one capsule, thereis no other choice than to use the size No. 1 capsule (major axis:approx. 19.1 mm and minor axis: 6.9 mm) or larger one.

[0007] Currently, capsules available for pharmaceutical use are suppliedin 8 sizes, i.e., the hard capsules are numbered from the size No. 000(the largest size with major axis: approx. 26.0 mm and minor axis: 10.0mm) to the size No. 5 (the smallest size with major axis: 11.1 mm andminor axis: 4.9 mm) (see: for example, Otsuka, A. et al. (Ed.),“SEIZAIGAKU (4th Edition)”, p. 91, Nankodo Co. Ltd., Japan, 1990;Murata, T. et al. (Ed.), “YAKUZAIGAKU (revised 5th Edition)”, p. 130,Nankodo Co. Ltd., Japan, 1997). However, when the patients take the drugorally, the smaller the capsule size and the fewer number of the capsuleper dose, the less the patient's burden, which leads improvement inpatient's compliance. Thus, in many cases, the capsules equal to orsmaller than size No. 2 (major axis: approx. 17.6 mm and minor axis: 6.4mm) have been favorably used. However, although it became possible tomake the co-micronized composition to reduce the amount of the activeingredient to ⅔, neither pharmaceutical formulation nor technology hasbeen found that allows 200 mg of fenofibrate which is a dose per day tobe filled into one capsule equal to or smaller than the size No. 2capsule.

DISCLOSURE OF THE INVENTION

[0008] Thus, the present inventor has extensively carried out a researchinto various pharmaceutical additives and their amounts to be admixedwhen the fenofibrate-containing composition, especially the fenofibratecomposition suitable for capsule preparations, is prepared, and studiedminimization of the capsule preparations without changing thebioavailability of fenofibrate which is the active ingredient. As aresult, the present inventor has succeeded in finding a novelcomposition which enables the reduction of a total additive amount to ½or less relative to the conventional capsule preparation containing theco-micronized composition (hereinafter, “conventional capsule”), byincorporating specific additives, and by specific compounding ratio witha co-micronized composition, and the production of minimized capsulepreparations (for example, down-sizing to shift conventional size No. 1capsules into size No. 2 or size No. 3, similarly size No. 2 capsulesinto size No. 3, and size No. 3 capsules into size No. 4). Said novelcomposition is expected to have equivalent bioavailability in vivo whencompared to the conventional capsules. A preferable condition forachieving the object of the present invention is described herein below.

[0009] The present invention provides a fenofibrate-containingcomposition comprising the following formula: (a) fenofibrate 100 partsby weight, (b) a solid surfactant 3 to 4 parts by weight, (c) lactose 1to 2 parts by weight, and (d) magnesium stearate 1 to 2 parts by weight,

[0010] in admixture with a binder and a disintegrator, wherein the sumof said binder and said disintegrator is 17 to 20 parts by weight, andthe fenofibrate and the solid surfactant are co-micronizates.

BRIEF DESCRIPTION OF THE DRAWING

[0011]FIG. 1 shows the results of Test Example 1.

BEST MODES FOR CARRYING OUT THE INVENTION

[0012] The fenofibrate used in the present invention has been previouslyco-micronized with the solid surfactant. The above solid surfactant usedincludes alkali metal sulfates of lauryl alcohol (e.g., sodium laurylsulfate), copolymers of ethylene oxide/propylene oxide (e.g.,polyoxyethylene (105) polyoxypropylene (5) glycol), sucrose fatty acidesters and the like. Among them, sodium lauryl sulfate is advantageouslyused.

[0013] The amount of the above solid surfactant is 3 to 4 parts byweight based on 100 parts by weight of fenofibrate. Both fenofibrate andthe solid surfactant are co-micronized by a micronizer typically used inmanufacturing preparations (e.g., a jet mill, a hammer mill, a vibratingball mill). Co-micronization can be carried out according to, forexample, the method described in Japanese Examined Patent PublicationNo. Hei 7-14876 (JP 7-14876, B (1995)). It is advantageous that theco-micronization is performed until obtaining powder where the meanparticle size of the micronized powder is less than 15 μm, preferablyless than 10 μm, and especially preferably less than 5 μm.

[0014] The above lactose could be any of those which are at the gradetypically used as pharmaceutical additives. The amount of the lactoseused is from 1 to 2 parts by weight based on 100 parts by weight offenofibrate. The above magnesium stearate could be any of those whichare at the grade typically used as pharmaceutical additives. The amountof the magnesium stearate used is from 1 to 2 parts by weight based on100 parts by weight of fenofibrate.

[0015] As the above binder, starch is advantageously used. The starchused for the invention may be any of those which are at the gradetypically used as pharmaceutical additives. The preferred starchincludes α-modified starch, partially α-modified starch, wheat starch,corn starch, potato starch and soluble starch. The especially preferablestarch is α-modified starch.

[0016] The above disintegrator preferably used includes crospovidone(otherwise known as: crosslinked poly vinylpyrrolidone), carmellose,sodium carmellose, potassium carmellose and the like which are at thegrade typically used as pharmaceutical additives. The especiallypreferable disintegrator is crospovidone. The total amount of the abovebinder and disintegrator is 17 to 20 parts by weight based on 100 partsby weight of fenofibrate.

[0017] The composition of the present invention is prepared by thefollowing process with adding the above additives to the aboveco-micronizate of fenofibrate and the solid surfactant:

[0018] The co-micronizate is mixed homogeneously with the additives, andsubjected to a granulation process to form granules. A lubricant isfurther added thereto, followed by admixing, and the resultant is filledup in a vacant capsule to give the capsulated preparation. Thegranulation method may be a dry-granulation method or a wet-granulationmethod.

[0019] The composition obtained by the present invention, afterformulated into a capsulated preparation, was subjected to a testaccording to the Dissolution Test as set forth in “The JapanesePharmacopoeia, 13 Edition” (JP XIII) as described herein below.Consequently, for the composition obtained in the invention, even thoughan amount of the additives used was reduced to approximately ½ or less,no difference in a dissolution rate was found as compared with theconventional capsule preparations disclosed in Japanese Examined PatentPublication No. Hei 7-14876 (JP 7-14876, B (1995)), suggesting that itexhibits good bioavailability.

EXAMPLES

[0020] Described below are examples, including a comparative example anda test example, of the present invention which are provided only forillustrative purposes, and not to limit the scope of the presentinvention. All of the examples, the comparative example and the testexample were carried out or can be carried out, unless otherwisedisclosed herein specifically, by standard techniques which are wellknown and conventional to those skilled in the art.

Example 1

[0021] According to the preparation example I in Japanese ExaminedPatent Publication No. Hei 7-14876 (hereinafter referred to “PREPARATIONI”), granules were prepared via a co-micronizing process of fenofibrateand sodium lauryl sulfate, wherein the formulation used was as follows:

[0022] Formula (in a capsule; total amount: 250.0 mg) Fenofibrate 200.0mg Sodium lauryl sulfate 7.0 mg Lactose 3.0 mg Magnesium stearate 3.0 mgα-Modified starch 30.0 mg Crospovidone 7.0 mg

[0023] The granules thus obtained were filled into size No. 2 capsules.

Example 2

[0024] In the same manner as in Example 1, granules were prepared via aco-micronizing process of fenofibrate and sodium lauryl sulfate, whereinthe formulation used was as follows:

[0025] Formula (in a capsule; total amount: 250.0 mg) Fenofibrate 200.0mg Sodium lauryl sulfate 7.0 mg Lactose 3.0 mg Magnesium stearate 3.0 mgα-Modified starch 30.0 mg Low substituted hydroxypropyl cellulose 7.0 mg

[0026] The granules thus obtained were filled into size No. 2 capsules.

Example 3

[0027] In the same manner as in Example 1, granules were prepared via aco-micronizing process of fenofibrate and sodium lauryl sulfate, whereinthe formulation used was as follows:

[0028] Formula (in a capsule; total amount: 250.0 mg) Fenofibrate 200.0mg Sodium lauryl sulfate 7.0 mg Lactose 5.0 mg Magnesium stearate 3.0 mgα-Modified starch 25.0 mg Crospovidone 10.0 mg

[0029] The granules thus obtained were filled into size No. 2 capsules.

Comparative Example 1

[0030] In the same manner as in Example 1, granules were prepared via aco-micronizing process of fenofibrate and sodium lauryl sulfate, whereinthe formulation used was as follows:

[0031] Formula (in a capsule; total amount: 350.0 mg) Fenofibrate 200.0mg Sodium lauryl sulfate 7.0 mg Lactose 101.0 mg Magnesium stearate 5.0mg α-Modified starch 30.0 mg Crospovidone 7.0 mg

[0032] The granules thus obtained were filled into size No. 1 capsules.

Test Example 1 Dissolution Test

[0033] <Test Method>

[0034] According to the Dissolution Test, Method 2 (Puddle method) underthe “General Tests, Processes and Apparatus” as set forth in “JP XIII”,the dissolution test for the capsules obtained in Example 1 andComparative Example 1 was carried out using 1000 mL of 0.1 mol/L sodiumlauryl sulfate as a dissolution medium at 50 rpm/min.

[0035] <Results>

[0036] The results are shown in FIG. 1. As is obviously shown in FIG. 1,no significant difference in the dissolution profile of fenofibrate wasobserved between Example 1 and Comparative Example 1.

Industrial Applicability

[0037] As aforementioned, the fenofibrate-containing composition of thepresent invention retaining enhanced bioavailability when compared toconventional capsule preparations, allows reduction of additive amountsto ½ or less, and makes it possible to provide minimized capsules whichcan be easily taken by patients orally. Stating more specifically, theco-micronized fenofibrate composition containing 200 mg of fenofibrateconventionally requires larger capsules (e.g., size No. 1 capsules);however, the present invention enables the co-micronized fenofibratecomposition to be filled into smaller capsules (e.g., size No. 2 or No.3 capsules).

[0038] While the present invention has been described specifically indetail with reference to certain embodiments and examples thereof, itwould be apparent that it is possible to practice it in other forms. Inlight of the disclosure, it will be understood that variousmodifications and variations are within the spirit and scope of theappended claims.

What is claimed is:
 1. A fenofibrate-containing composition comprising the following formulation: (a) fenofibrate 100 parts by weight, (b) a solid surfactant 3 to 4 parts by weight, (c) lactose 1 to 2 parts by weight and (d) magnesium stearate 1 to 2 parts by weight

in admixture with a binder and a disintegrator, wherein the sum of said binder and said disintegrator is 17 to 20 parts by weight, and the fenofibrate and the solid surfactant are co-micronizates.
 2. The composition according to claim 1, wherein the solid surfactant is sodium lauryl sulfate.
 3. The composition according to claim 2, wherein the binder is starch.
 4. The composition according to claim 3, wherein the disintegrator is crospovidone. 